The Ras oncogene is one of the most frequently mutated oncogenes in human cancers. Active Ras mutation is strongly associated with human cancers. Extensive efforts have been made to identify Ras inhibitor as a putative cancer therapy with the most promising progress made on the development of farnesyltransferase inhibitors. However, these farnesyltransferase inhibitors will inhibit the function of both the wild type Ras and mutant Ras as well as many small GTPases. Recently, we have demonstrated that the wild type Ras is tumor suppressive and this proposal will demonstrate that wild type Ras can actually be used as a tumor suppressor to inhibit cancer development. Accordingly, two specific aims are proposed to test our hypothesis. The first specific aim will evaluate the correlation between the presence of a mutant K-ras allele and the loss of wild type K-ras allele in human lung tumors. The second specific aim will examine the effect of the wild type K-ras allele on tumorigenesis and growth characteristics of lung tumor cell lines. Understanding the newly discovered role of the wild type Ras will have immediate and important implications for the development of various Ras-directed gene therapy and drug development. PROPOSED COMMERCIAL APPLICATION: Not available